Shifting their focus to the advanced disease setting, panelists provide a comprehensive overview on systemic treatment modalities used in biliary tract cancers.
Milind Javle, MD: I want to switch gears to systemic therapy. Ruth, we’ve had gemcitabine-cisplatin for over a decade and several trials. Could you give us a high-level view of the problem in terms of drug development in biliary tract cancer in the first and second lines? Why you think we’ve had negative trials, other than the fact that this is a difficult disease?
Aiwu Ruth He, MD: Over the years, we’ve participated in many trials. We’ve seen very promising phase 1 and 2 studies and high response rates, but then they don’t pan out. Some of the challenges are about this being a very heterogeneous disease. Also, patients tend to get very sick when they have advanced-stage disease, so medical management of the obstruction infection becomes challenging for those patients. In the last couple of years, we’ve made progress, and we have a lot of more options. Ten years ago, we had gemcitabine-cisplatin in a positive phase 3 trial. Then we looked at the VEGF pathway. We looked at the EGFR pathway. We looked at MET and MEK. We’ve looked at all those pathways, and we’ve had a lot of negative trials.
With more understanding of the tumor biology, I view all the trials in 3 areas. We’re making progress on chemotherapy combinations. We have gemcitabine-cisplatin, and we have FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] as a second-line [therapy]. The NIFTY study, which is a randomized phase 2 study, supports the liposomal irinotecan–5-FU [5-fluorouracil] combination as 1 of the second-line options. The NAPOLI-2 study tests the same combination in the Western population in the United States. It’s still ongoing, so we should have more data on that.
We have a triplet that was initially developed at [The University of Texas] MD Anderson [Cancer Center], gemcitabine-cisplatin-Abraxane. It shows a very high response rate and a very promising survival in the phase 2 study. It’s now being tested in a phase 3 trial. This has made it to the NCCN [National Comprehensive Cancer Network] Guidelines. I use it because of the very high response rate for downstaging in patients who are borderline resectable. We’ve seen some good success for robust patients, but that’s at the cost of some toxicities.
Then I looked at immunotherapy. This is the beginning. We’re starting to see positive data from immunotherapy. The additional immunotherapy in combination with chemotherapy is being tested. We hope to see more promising data following the positive TOPAZ-1 study. Then there’s precision oncology, which you presented earlier. About 40% to 50% of cholangiocarcinoma has targetable mutations. We see a lot more targeted therapy, and we know how to better use to select patients for those therapies. It’s a very exciting time. I can go into more detail, but I’ll stop here.
Milind Javle, MD: Ruth, to pin you down a little, should we be lumping or splitting? Should we be including all biliary tract cancers in a single trial of chemotherapy, or do you think there’s rationale to split it into different biliary groups?
Aiwu Ruth He, MD: That’s a very interesting question. It’s a balance. We can see from the promising data on triplet chemotherapy that it provides benefit in a good group of patients, and that’s not a split situation. For immunotherapy biomarkers, how can we define the patients who will benefit and have a “hot” tumor? How can we convert a “cold” tumor into a “hot” tumor? Select all those patients? I don’t think we have enough information to do that, but you can see the very promising response rate of 30% to 40% from FGFR inhibitor, in patients with FGFR2 fusion. That support is split. With more options, [we now think about] when to do what. In the future, we’ll need to profile everybody.
We’re testing precision oncology as targeted therapy in the frontline setting, so we should have more data. With additional data, we may need to split in the front line. Find the targeted mutation and the profile that favors immunotherapy. In the second line or future lines of therapy, we may need to test them more. I had a couple of patients with Y90 [yttrium 90] and hypertrophy of the other side of the lobe of liver. [They were] robust up front, even unresectable, with a drop-off of CA [cancer antigen] 19-9. I attempt to do the triplet of chemotherapy and then try to bring the patient to surgery. We’ve seen good results from that. It’s a very complex answer. With biomarker development and more options, we can say at what setting we should lump them together at what setting we should split.
Transcript edited for clarity.